Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a group of unrelated Danish patients with familial hypercholesterolemia (FH) we recently reported two common low-density lipoprotein (LDL) receptor mutations, W23X and W66G, accounting for 30% of the cases. In this study, we describe another common LDL receptor mutation, a G to C transition at cDNA position 1730 in exon 12, causing a tryptophan to serine substitution in amino acid position 556 (W556S). In the Danish patients, the W556S mutation was present in 12% of 65 possible mutant alleles. The pathogenicity of the W556S mutation, which is located in one of the five conserved motifs Tyr-Trp-Thr-Asp in the epidermal growth factor homology region, was studied in transfected COS-7 cells expressing normal and mutant LDL receptor cDNAs. Results obtained by immunofluorescence flow cytometry and confocal microscopy, as well as by immunoprecipitation, were compatible with complete retention of the mutant protein in the endoplasmic reticulum. The transport-defective W556S mutation and the W23X and W66G mutations seem to account for about 40% of the LDL receptor defects in Danish families with FH.
Atherosclerosis 1997 May
PMID:A common W556S mutation in the LDL receptor gene of Danish patients with familial hypercholesterolemia encodes a transport-defective protein. 918 Feb 46

Small, dense LDL particles have been associated with an increased risk of coronary artery disease. In order to assess the potential contribution of the genotype of the LDL receptor to LDL particle size heterogeneity in familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of LDL particles in a large cohort of FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. LDL particles were characterized by polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. LDL-peak particle diameter (LDL-PPD), representing the most abundant LDL particle subpopulation, was significantly smaller in FH heterozygotes carrying a negative-receptor mutation than in subjects carrying a defective-receptor mutation (negative-receptor = 257.3 +/- 4.1 A versus defective-receptor = 259.0 +/- 4.3 A, p = 0.0006). No significant difference in plasma CETP concentrations was found between these two genotypic groups. Moreover, compared with controls having low triglyceride levels, negative-receptor subjects with high triglyceride levels had a relative risk of 19.6 (p < 0.0001) of having small, dense LDL particles while this risk was not significantly increased among defective-receptor subjects. Multivariate analysis showed that the LDL receptor status accounted for 5.7% of the variance in the LDL-PPD after adjustment for covariates. These results suggest that the genotype of the mutant LDL receptor allele was independently associated with variations in LDL-PPD and could partly explain why negative-receptor FH heterozygotes may be at greater risk of cardiovascular disease than defective-receptor FH subjects.
Atherosclerosis 2006 Jan
PMID:Genotype of the mutant LDL receptor allele is associated with LDL particle size heterogeneity in familial hypercholesterolemia. 1589 84

The long-term effect of elevated levels of human apolipoprotein AI (apoAI) on atherosclerosis was assessed using human apoAI transgenic mice on a double mutant LDL receptor-deficient (LDLr-/-) and mouse apoAI-deficient (apoAI-/-) background. When they were fed a high fat diet, atherosclerosis in transgenic human apoAI, LDLr-/-, apoAI-/- mice (huapoAITg) was compared with LDLr-/- mice that expressed normal amounts of apoAI (msapoAI) or LDLr-/- mice that lacked mouse apoAI (noapoAI). The atheroprotective effect of human apoAI was demonstrated by a greater than six-fold inhibition in lesion areas in the aortic wall and heart valves compared to the two control strains after 27 or 36 weeks. Plasma apoAI concentrations in huapoAITg mice were considerably higher than in msapoAI mice (600 and 37 mg/dL, respectively). The human apoAI transgene led to several plasma HDL subpopulations, with high levels of prebeta-HDL and a significant decrease in total plasma cholesterol. This was observed without a change in total HDL cholesterol levels. Thus, elevated levels of human apoAI in LDL receptor-deficient mice lacking mouse apoAI conferred profound protection against diet-induced over extended periods of time.
Atherosclerosis 2006 Dec
PMID:Overexpression of human ApoAI transgene provides long-term atheroprotection in LDL receptor-deficient mice. 1642 56